Data from PLK1 Inhibition Induces Synthetic Lethality in Fanconi Anemia Pathway–Deficient Acute Myeloid Leukemia

• DOI: 10.1158/2767-9764.c.7815407
• Publication Date: 2025-05-13T16:35:49Z
• Authors: Aditya S. Sheth; Ka-Kui Chan; Sheng Liu; Jun Wan; Steve P. Angus; Steven D. Rhodes; Dana K. Mitchell; Christopher Davis; Maya Ridinger; Peter J. Croucher; Amer M. Zeidan; Aruna Wijeratne; Shaomin Qian; Ngoc Tung Tran; Elizabeth A. Sier...
• Keywords: Synthetic Lethality; Lethality

<div>Abstract<p>Overall survival of acute myeloid leukemia (AML) remains limited. Inhibitors the master mitotic kinase PLK1 have emerged as promising therapeutics, demonstrating efficacy in an undefined subset patients with AML. However, clinical success inhibitors hindered by a lack predictive biomarkers. The Fanconi anemia (FA) pathway, tumor-suppressive network comprised at least 22 genes, is frequently mutated sporadic In this study, we demonstrate that FA pathway disruption sensitizes AML cells to inhibition. Mechanistically, identify novel interactions between and both FANCA FANCD2 centromeres. We inhibition impairs recruitment centromeres, induces damage chromosomes, triggers collapse FANCA-deficient cells. Our findings indicate targets vulnerabilities specific pathway–deficient implicate mutations potential biomarkers for identification likely benefit from inhibitors.</p>Significance:<p>This work demonstrates mutations, which are observed AML, induce hypersensitivity inhibition, providing rationale synthetic lethal therapeutic strategy patient population.</p></div>